A group of experimental systems which allow the determination of quantitative endpoints in normal tissue and in tumors in the mouse will be used to search for methods which yield improved therapeutic ratios. Measurement of normal tissue damage to be applied include pulmonary lethality, esophageal lethality, renal lethality, whole brain lethality, intestinal crypt cell assay, skin reaction grade assay, and the mouse bone marrow CFU assay. Tumor endpoints to be applied include the use of the EMT6 mouse mammary tumor in vivo as a solid tumor, tumor located in the leg or flank, as pulmonary microcolonies, and as pulmonary macrocolonies. Assay methods will include in vivo treatment and in vitro assay, lung nodule assay, and regrowth delay time assay. Additional tumor systems to be employed include the Yuhas pulmonary carcinoma, the colon 26 and 36 carcinomas, the Lewis lung carcinoma, and the B16 melanoma. Using these systems which have been extensively employed and to a certain extent developed in our laboratory, the damage to normal tissue vs tumor will be determined and combinations or individual radiation regimens yielding improved tumor kill for a given normal tissue damage determined. The therapeutic ratio so measured will be compared for various tumor types and for various specific critical normal tissues. Methods of enhancing tumor damage vs normal tissue damage to be explored include the effect of multiple or hyperfractionation of the radiation dose, the effect of alterations in radiation dose rate, the effects of anti-cancer chemotherapeutic agents, the effects of chemical radiation protective of sensitizing compounds, the relative effectiveness of high LET heavy particles, including 15 MeV neutrons, helium ions, carbon, neon, and argon ions, and the effects of hyperthermia on tumor and normal tissue.